CREM Marks TCR-Driven T-Cell Activation and Associates with Favorable Prognosis in Papillary Thyroid Carcinoma: A Single-Cell and Bulk Transcriptomic Study

Although papillary thyroid carcinoma (PTC) is widely considered an immunologically cold tumor, detectable T-cell infiltration can influence disease progression in selected patients. Previous bulk analyses have linked cAMP-responsive element modulator (CREM) expression to a favorable progression-free interval and an inverse correlation with regulatory T-cell infiltration but have not resolved the cellular origin or functional state. In this study, we integrate single-cell RNA-sequencing data from a 23-sample PTC atlas with bulk Cancer Genome Atlas Thyroid Carcinoma (TCGA–THCA) validation. We show that CREM marks a T-cell receptor (TCR)-driven immediate early gene activation state in tumor-infiltrating T cells rather than a cAMP program; this state is consistently and modestly enriched within the FOXP3+ regulatory T-cell compartment, challenging the interpretation that bulk inverse Treg–CREM correlations reflect Treg-intrinsic repression. CREM-high T cells upregulate ANXA1, and permutation-controlled analysis identifies a candidate paracrine axis from CD4/CD8 T cells to the epithelial epidermal growth factor receptor (EGFR). At the bulk level, CREM expression correlates with reduced proliferation programs and is associated with a prolonged progression-free interval (multivariate HR 0.56, 95% CI 0.31–1.00, p = 0.050), with the effect direction preserved after immune and sex adjustment. Genome-wide differential expression and gene-set enrichment in an independent cohort (GSE193581) confirm that CREM-detected T cells are enriched for a TCR-driven immediate early transcriptional program, supporting the reinterpretation of CREM as a marker of TCR-driven IEG activation.